The histone chaperone Spt6 coordinates histone H3K27 demethylation and myogenesis

Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
The EMBO Journal (Impact Factor: 10.43). 03/2013; 32(8). DOI: 10.1038/emboj.2013.54


Histone chaperones affect chromatin structure and gene expression through interaction with histones and RNA polymerase II (PolII). Here, we report that the histone chaperone Spt6 counteracts H3K27me3, an epigenetic mark deposited by the Polycomb Repressive Complex 2 (PRC2) and associated with transcriptional repression. By regulating proper engagement and function of the H3K27 demethylase KDM6A (UTX), Spt6 effectively promotes H3K27 demethylation, muscle gene expression, and cell differentiation. ChIP-Seq experiments reveal an extensive genome-wide overlap of Spt6, PolII, and KDM6A at transcribed regions that are devoid of H3K27me3. Mammalian cells and zebrafish embryos with reduced Spt6 display increased H3K27me3 and diminished expression of the master regulator MyoD, resulting in myogenic differentiation defects. As a confirmation for an antagonistic relationship between Spt6 and H3K27me3, inhibition of PRC2 permits MyoD re-expression in myogenic cells with reduced Spt6. Our data indicate that, through cooperation with PolII and KDM6A, Spt6 orchestrates removal of H3K27me3, thus controlling developmental gene expression and cell differentiation.

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    • ". On the other hand, KDM6A has been directly linked to transcriptional elongation through its interaction with RNA Polymerase II via Spt6 [59]. Furthermore, PRC2 specifically resides at genes encoding developmental regulators (e.g., HOX genes) and its absence leads to embryonic stem cell differentiation defects and a delay in the loss of pluripotency [60]. "
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    • "Interestingly, JMJD3 has also been shown to interact with the H3K36 methyltransferase SetD2 (Chen et al, 2012), which mediates H3K36-trimethylation in the body of transcribed genes. While the association of Spt6 and UTX with SetD2 was not examined in myoblasts, loss of Spt6 leads to a decrease in H3K36me3 accumulation within muscle genes (Wang et al, 2013). This would suggest that an ability to associate with additional components of the transcriptional elongation machinery is likely conserved between UTX and JMJD3. "
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    ABSTRACT: The histone chaperone Spt6 is known to facilitate transcriptional elongation while preventing spurious initiation of transcription within the coding region of genes. A recent publication in The EMBO Journal (Wang et al, 2013) identifies an additional mechanism by which Spt6 promotes gene expression by demonstrating that it tethers the histone demethylase UTX/KDM6A to the elongating RNA Polymerase II, thereby enabling the removal of repressive H3K27me3 marks within developmentally important muscle genes.
    Full-text · Article · Mar 2013 · The EMBO Journal
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